FR2781226A1 - N-(Alkyl carbonyl benzodioxolyl and benzodioxanyl) piperidinyl and pyrrolidinyl dihydro pyridine-3,5-diesters having calcium blocking activity useful for treating angina - Google Patents

Abstract

N-(alkyl carbonyl benzodioxolyl and benzodioxanyl) piperidinyl and pyrrolidinyl dihydro pyridine-3,5-diester derivatives (I) are new. N-(alkyl carbonyl benzodioxolyl and benzodioxanyl) piperidinyl and pyrrolidinyl dihydro pyridine-3,5-diester derivatives of formula (I) and their salts are new. n = 1 or 2; m = 3 or 4; p = 1 or 2. Independent claims are also included for: (1) the preparation of (I); and (2) the intermediates of formula (III).

Description

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1
The present invention relates to novel 1,4-dihydropyridine derivatives that can be used therapeutically, in particular as antiangorous agents.

 Various 1,4-dihydropyridine derivatives have already been described. Thus, in particular, in FR 2 218 107, various 2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid esters, and in particular ester 2, have already been described [ methyl (phenyl-methyl) amino] ethyl known as nicardipine.

et R2 représente un groupe choisi parmi les groupes 2,4,6-triméthoxyphényle, 2thiényle et phényle. Other derivatives of 1,4-dihydropyridine having in position 3 a chain of the type: -COO-A - (CH 2) 3 - C -R 2 has also been described in EP-A-0494 816.
Wherein A represents a group selected from groups of formula.

and R2 represents a group selected from 2,4,6-trimethoxyphenyl, 2-thienyl and phenyl.

 The present invention aims to provide new derivatives of 1,4-dihydropyndine which are calcium channel blockers and which have improved properties compared to those of compounds corresponding to the formula described in EP-A-0 494 816.

dans laquelle : n = 1 ou 2 m = 3 ou 4 The present invention thus relates to compounds of formula:

in which: n = 1 or 2 m = 3 or 4

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 p = 1 or 2 and their addition salts with pharmaceutically acceptable acids.

 The addition salts with pharmaceutically acceptable acids refer to the salts which give the biological properties of the free bases, without having any undesirable effect. These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.

avec un alcool de formule

dans laquelle n, m et p ont la signification donnée précédemment. The compounds of formula # can be obtained by the reaction of the acid of formula:

with an alcohol of formula

in which n, m and p have the meaning given above.

 The addition salts are obtained conventionally by reacting the compound of formula I with a pharmaceutically acceptable acid in a suitable solvent. Conversely, the bases can be obtained from the addition salts by treatment with a strong base.

 The acid of formula II can be prepared as described in EP-A-0 494 816 or as described in EP-A-0 680 952.

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avec un dérivé chloré de formule :

The alcohols of formula III may be obtained by reaction of a compound of formula:

with a chlorinated derivative of formula:

The chlorinated derivatives of formula (V) can themselves be prepared according to the following scheme.

 The following examples illustrate the preparation of the compounds according to the invention.

1 - Preparation of chlorinated derivatives of formula V
11-) Preparation of 4-chloro-1- (1,4-benzodioxan-6-yl) -1-butanone.

 In a solution maintained at +5 of 1 mole of 1,4-benzodioxane and 1.08 mole of 4-chlorobutyryl chloride in 750 ml of dry benzene, a solution of 1.16 mol of tin tetrachloride is cast in 1 h 30 min. in 400 ml of dry benzene. Stirring is allowed to return to room temperature for 3 hours and the reaction medium is thrown on 1500 ml of 2N hydrochloric acid. The mixture is stirred for one hour and the organic phase is decanted and washed with water. After drying over dry sodium sulphate and

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 After evaporation of the solvent, the residue was purified by crystallization from cyclohexane-5: benzene-1 to give 0. 81 moles of a yellow powder.

Finst (Kofler) = 72 Yield = 81%
The following products are prepared according to this method:
12-) 5-Chloro-1- (1,4-benzodioxan-6-yl) -1-pentanone from 1,4-benzodioxane and 5-chlorovaleryl chloride.

13-) 4-chloro-1- (1,3-benzodioxol-5-yl) -1-butanone from 1,3-benzodioxole and 4-chlorobutyryl chloride (Yield = 95%)
14-) 5-Chloro-1- (1,3-benzodioxol-5-yl) -1-pentanone from 1,3-benzodioxole and 5-chlorovaleryl chloride.

2- Preparation of aminoalcohols of formula III
21-) Preparation of 1- (1,4-benzodioxan-6-yl) -4- (3hydroxypiperidino) -1-butanone.

 In a refluxing suspension of 1 mole of 3-hydroxy piperidine, 1.5 moles of potassium carbonate and in the presence of 0.15 moles of potassium iodide in 600 ml of acetonitrile, are introduced in fractions over 30 minutes: 1 mol of 4-chloro-1- (1,4-benzodioxan-6-yl) -1-butanone (compound 11-). The reflux is maintained for 4 h, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is treated with an acid / base passage and after drying over dry sodium sulphate and evaporation of the solvent, the residue is purified by washing in diisopropyl ether to give: 0.52 mol of a beige powder.

Yield = 52%

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22-)-1-( 1 ,4-benzodioxanne-6-yl)-5-(3-hydroxypiperidino )-1-pentanone à partir du composé -12- et de la 3-hydroxy pipéridine. Finst (Kofler) = 110
The following products are prepared according to this method:

22-) - 1- (1,4-Benzodioxan-6-yl) -5- (3-hydroxypiperidino) -1-pentanone from the compound -12- and 3-hydroxypiperidine.

24-)-1-(1 ,4-benzodioxanne-6-yl)-5-[(3R)(3-hydroxypiperidino)]-1- pentanone à partir du composé-12- et de la (3R) 3-hydroxy pipéridine.

25-)1-(1 ,4-benzodioxanne-6-yl)-4-[(35)(3-hydroxypiperidino )]-1- butanone à partir du composé -11- et de la (3S) 3-hydroxy pipéridine. [Rdt=50%; Finst(Kofler) = 105 ]

26-)1-(1 ,4-benzodioxanne-6-yl)-4-[(3R)(3-hydroxypiperidino )]-1- butanone à partir du composé -11- et de la (3R) 3-hydroxy pipéridine. [Rdt=53%; Finst(Kofler) = 105 ]

27-)-1-(1,4-benzodioxanne-6-yl )-5-(3-hydroxypyrrolidino)-1-pentanone à partir du composé -12- et de la 3-hydroxy pyrrolidine. 23 -) - 1- (1,4-Benzodioxan-6-yl) -5 - [(3S) (3-hydroxypiperidino)] - pentanone from compound 12 and (3S) 3-hydroxy piperidine.

24 -) - 1- (1,4-Benzodioxan-6-yl) -5 - [(3R) (3-hydroxypiperidino)] - pentanone from compound 12 and (3R) 3-hydroxy piperidine.

25-) 1- (1,4-Benzodioxan-6-yl) -4 - [(35) (3-hydroxypiperidino)] -1-butanone from the compound -11- and (3S) 3-hydroxypiperidine . [Yield = 50%; Finst (Kofler) = 105]

26-) 1- (1,4-Benzodioxan-6-yl) -4 - [(3R) (3-hydroxypiperidino)] -1-butanone from the compound -11- and (3R) 3-hydroxy piperidine . [Yield = 53%; Finst (Kofler) = 105]

27-) - 1- (1,4-Benzodioxan-6-yl) -5- (3-hydroxypyrrolidino) -1-pentanone from the compound 12- and 3-hydroxy pyrrolidine.

28 -) - 1- (1,4-Benzodioxan-6-yl) -5 - [(3S) (3-hydroxypyrrolidino)] - 1 -pentanone from 12-compound and (S) 3-hydroxy pyrrolidine.

 29 -) - 1- (1,4-Benzodioxan-6-yl) -5 - [(3R) (3-hydroxypyrrolidino)] - pentanone from compound 12 and (R) 3-hydroxy pyrrolidine.

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210 -) - 1- (1,4-Benzodioxan-6-yl) -4- (3-hydroxypyrrolidino) -1-butanone from the compound -11- and 3-hydroxy pyrrolidine.

211 -) - 1- (1,4-Benzodioxan-6-yl) -4 - [(3S) (3-hydroxypyrrolidino)] - 1butanone from the compound -11- and (S) 3-hydroxy pyrrolidine.

212 -) - 1- (1,4-Benzodioxan-6-yl) -4 - [(3R) (3-hydroxypyrrolidino)] -1-butanone from the compound -11- and (R) 3-hydroxy pyrrolidine.

213 -) - 1- (1,3-benzodioxol-5-yl) -4- (3-hydroxypyrrolidino) -1-butanone from 13-compound and 3-hydroxy pyrrolidine
214 -) - 1- (1,3-benzodioxol-5-yl) -4 - [(3S) (3-hydroxypyrrolidino)] - 1butanone from 13-compound and (3S) 3-hydroxy pyrrolidine.

215 -) - 1- (1,3-Benzodioxol-5-yl) -4 - [(3R) (3-hydroxypyrrolidino)] - 1-butanone from 13-compound and (3R) 3-hydroxy pyrrolidine.

 216 -) - 1- (1,3-benzodioxol-5-yl) -5- (3-hydroxypyrrolidino) -1-pentanone from 14-compound and 3-hydroxy pyrrolidine.

217 -) - 1- (1,3-benzodioxol-5-yl) -5 - [(3S) (3-hydroxypyrrolidino)] -1-pentanone from compound-14- and (S) 3-hydroxy pyrrolidine.

218-) -1- (1,3-benzodioxol-5-yl) -5 - [(3R) (3-hydroxypyrrolidino)] pentanone from the compound -14- and (R) 3-hydroxy pyrrolidine.

219 -) - 1- (1,3-benzodioxol-5-yl) -4- (3-hydroxypiperidino) -1-butanone from 13-compound and 3-hydroxypiperidine (Yield = 22%)

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220-)-1-(1 ,3-benzodioxole-S-yl)-4-[(3S)(3-hydroxypiperidino)]-1- butanone à partir du composé-13- et de la (S) 3-hydroxy pipéridine. [Rdt=27%; Finst(Kofler) = 102 ]
221-)-1- (1,3-benzodioxole-5-yl)-4-[(3R)(3-hydroxypiperidino)]-1butanone à partir du composé-13- et de la (R) 3-hydroxy pipéridine. [Rdt=33%; Finst(Kofler) = 105 ]

222-)-1-(1,3-benzodioxole-5-yl )-5-(3-hydroxypipéridino)-1-pentanone à partir du composé-14- et de la 3-hydroxy pipéridine

223-)-1-( 1 ,3-benzodioxole-S-yl)-S-[(3S)(3-hydroxypipéridino )]-1- pentanone à partir du composé-14- et de la (3S) 3-hydroxy pipéridine

224-)-1-( 1 ,3-benzodioxole-S-yl)-S-[(3R)(3-hydroxypipéridino )]-1- pentanone à partir du composé-14- et de la (3R) 3-hydroxy pipéridine.

220 -) - 1- (1,3-benzodioxol-5-yl) -4 - [(3S) (3-hydroxypiperidino)] - 1-butanone from 13-compound and (S) 3-hydroxy piperidine. [Yield = 27%; Finst (Kofler) = 102]
221 -) - 1- (1,3-benzodioxol-5-yl) -4 - [(3R) (3-hydroxypiperidino)] - 1butanone from 13-compound and (R) 3-hydroxy piperidine. [Yield = 33%; Finst (Kofler) = 105]

222 -) - 1- (1,3-benzodioxol-5-yl) -5- (3-hydroxypiperidino) -1-pentanone from 14-compound and 3-hydroxy piperidine

223 -) - 1- (1,3-benzodioxol-5-yl) -S - [(3S) (3-hydroxypiperidino)] - pentanone from compound-14- and (3S) 3-hydroxy piperidine

224 -) - 1- (1,3-benzodioxol-5-yl) -S - [(3R) (3-hydroxypiperidino)] - pentanone from 14-compound and (3R) 3-hydroxy piperidine.

3- Preparation of Dihydropyridines of Formula #
31-) Preparation of N- [4- (1,4-benzodioxan) -6- (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate yl) -4-oxobutyl] piperidine-3'-yl (CRL 42816) In a solution of 1.10 mol of oxalyl chloride in 1000 ml of dichloromethane, fractions are introduced in fractions: 1 mol of 4- (R) 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid and stirred at room temperature for 3 h under a stream of nitrogen. The reaction medium is diluted with 800 ml of dichloromethane and 1 mole of 1- (1,4-benzodioxan-6-yl) -4- (3-hydroxypiperidino) -1-butanone (compound-21) is introduced in portions over 15 minutes. ) in hydrochloride form and then stirred under a stream of nitrogen for one hour. The reaction medium is washed

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 successively with water and 2N sodium hydroxide, the organic phase, dried over dry sodium sulfate and the solvent evaporated to give an orange oil.

After purification of this product, it is obtained by passing through a column of silica and eluting with dichloromethane-99 / isopropanol-1: 0.57 mol of a yellow powder.

Yield = 57% [a] D + 14 (c = 1.25, MeOH)
The following products are prepared according to this method:
N- [4- (1,4-benzodioxan) -32- (4S, 3'R) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate 6-yl) -4-oxobutyl] -piperidine-3'-yl (CRL 42925) from the compound-26- and 4 (R) -acid 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1 4-dihydropyridine-3-carboxylic acid (Yield = 60%; [a] o - 23 (c = 1 25, MeOH)
N- [4- (1,4-benzodioxan) -6- (4S, 3'S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate 4-oxobutyl] piperidine-3'-yl (CRL 42943) from the compound 25- and 4 (R) -5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4 -dihydropyridine-3-carboxylic acid. (Yield = 57%; [[alpha]] D +66 (c = 1.26; MeOH)
N- [4- (1,3-benzodioxol-5-yl) 34- (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinedicarboxylate 4-oxobutyl] piperidine-3'-yl (CRL 42820) from the compound-219- and 4 (R) -5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine -3-carboxylic acid. (Yield = 31%; [[alpha]] D + 14 (c = 1.24; MeOH)

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N- [4- (1,3-benzodioxole) N- [4- (1,3-benzodioxole) -3- (4S, 3'R) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate 5-yl) -4-oxobutyl] piperidine-3'-yl from the compound -221- and 4 (R) -5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine -3-carboxylic acid. (Yield = 59%, [[alpha]] D -22 (c = 1.26, MeOH).

N- [4- (1,3-benzodioxole) 36- (4S, 3'R) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate 5-yl) -4-oxobutyl] piperidine-3'-yl from the compound-220- and 4 (R) -5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine -3-carboxylic acid. (Yield = 26%; [[alpha]] D +57 (c = 1.21; MeOH)
Pharmacological results highlighting the advantageous properties of the compounds of the invention will be given below.

1) Anti-calcium activity by measuring affinity for DHP sites of rat heart ventricles
The affinity of the compounds for the DHP sites of the cardiac ventricles is measured from a membrane preparation of the receptors, preparation obtained after dissection of the ventricles, homogenization followed by double centrifugation (48000 g, 15 min, 4 C).

 These membrane preparations are brought into contact with the specific radioactive ligand (+) [3H] -PN 200-110 and the compound to be studied, at different concentrations. The suspension is stirred for 30 minutes at a temperature of 30 ° C. The reaction is then stopped by filtration using a Harvester type system. The filter is introduced into a counting vial containing scintillant liquid. The radioactivity present on each filter is then measured by counting in a liquid scintillation counter.

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 The intensity of the binding to the membrane receptors is defined by the concentration (molar) of the test compound which is necessary to displace 50% of the amount of the specific ligand (+) [3H] -PN 200-110 previously bound to the DHP sites. . This concentration is the Cl50 concentration.

 The results expressed in Cl50 are given in the table summarizing the pharmacological and hemodynamic results.

2) Anticalcic activity by measuring the antagonism of the contraction of the isolated rat aorta by KCI
The technique used uses a ring of arterial vascular tissue taken from the thoracic aorta of the rat and then maintained in survival in aerated Krebs bicarbonate buffer, and subjected to an initial tension of 2.0 g.

The introduction of potassium chloride KCl (in a volume of 300 l) at the concentration of 5.10-2 MI-1 in the Krebs buffer bath generates a sustained contraction whose amplitude (isometric tension) is antagonized by the addition of a solution of the studied compound of increasing concentrations, each addition being carried out every 5 minutes. The molar concentration of the test compound is then calculated which reduces by 50% the maximum contraction observed under KCl. This concentration is the 50% inhibitory concentration (or Clso).

 The results expressed in Cl50 are given in the table summarizing the pharmacological and hemodynamic results.

3) Effect on the coronary flow of the anesthetized dog
The animals receive IV increasing doses of compounds every 30 minutes. The effect on coronary flow is evaluated by its percentage of maximum variation after each dose.

 The minimum active rate on coronary flow is the dose that increases basal coronary onset by 50%.

 The results are presented in the summary table below.

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4) Therapeutic margin
The therapeutic margin is defined as the ratio between the minimum arrhythmogenic dose and the dose that increases basal coronary flow by 50% (this dose is called the "minimum active dose on coronary flow").

 For each compound in the anesthetized dog, the minimum arrhythmogenic IV doses were determined (see summary table) and the arrhythmogenic dose / active dose ratio on the coronary flow (therapeutic margin) was determined.

BOARD

<Tb>
<tb> Profile <SEP> in <SEP> vitro <SEP> Profile <SEP> in <SEP> vivo
<tb> Link <SEP> Site <SEP> Contraction <SEP> Minimum <SEP> Minimum <SEP> Active <SEP> at <SEP>
<tb> Ex <SEP> CRL <SEP> DHP <SEP> Kcl <SEP> Aorta <SEP> dog <SEP> (g / kg)
<tb> Administration <SEP> iv
<tb> Clso <SEP> (nM) <SEP> Clso <SEP> (nM) <SEP> t <SEP> DC <SEP> Arrhythmia <SEP> Margin
<tb> therapeutic
<tb> 31 <SEP> 42816 <SEP> 9 <SEP> 570 <SEP> 40 <SEP> 320 <SEP> 8
<tb> 32 <SEP> 42925- <SEP> - <SEP> 10 <SEP> 640 <SEP> 64
<tb> 34 <SEP> 42820 <SEP> 5 <SEP> 110 <SEP> 10 <SEP> 640 <SEP> 64
<Tb>

The present invention also relates to therapeutic compositions comprising as active ingredient a compound of formula 1 or one of its addition salts with pharmaceutically acceptable acids.

 The therapeutic compositions according to the invention may be administered to humans or animals orally or parenterally.

 They can be in the form of solid, semi-solid or liquid preparations. As an example, mention may be made of tablets, capsules, suppositories, injectable solutions or suspensions, as well as slow forms and slow release implanted forms.

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 In these compositions, the active ingredient is generally mixed with one or more conventional pharmaceutically acceptable excipients well known to those skilled in the art.

 The amount of active ingredient administered obviously depends on the patient being treated, the route of administration and the severity of the disease.

 The compositions according to the invention can be used in particular for treating the cardiovascular manifestations of stable angina (antiangorous drugs).

Claims (5)

 wherein: n = 1 or 2 m = 3 or 4 p = 1 or 2, and their addition salts with pharmaceutically acceptable acids.

 1. Compounds of formula: 2. Process for the preparation of a compound according to claim 1, comprising the reaction of the acid of formula:

 with an alcohol of formula:

 in which n, m and p have the meaning given in claim 1. 3. Therapeutic composition comprising, as active ingredient, a compound according to claim 1. <Desc / Clms Page number 14>  4. Compounds of formula

 in which n, m and p have the meaning given in claim 1. 5. Use of the compounds according to claim 1 for the manufacture of an antiangorous drug.